This invention relates to systems and methods for non-invasively determining physiological parameters related to the oxygenation status of a patient. More specifically, the invention is directed to systems and methods for the real time determination of parameters associated with global tissue oxygenation in a subject.
A problem that has long troubled physicians is how to accurately measure the oxygenation state of a patient""s tissues without resorting to an invasive procedure. This is important during many medical procedures because the physician needs to know when to administer medicaments or transfuse more blood into a patient. When the oxygenation state of a patient""s tissues is low, the physician may wish to transfuse more blood or other oxygen carriers to increase the oxygen transportation rate and maintain adequate cellular respiration.
In the surgical and postoperative settings, decisions regarding the need for blood transfusion normally are guided by hemoglobin (Hb) or hematocrit levels (Hct). Hematocrit is typically defined as the percentage by volume of packed red blood cells following centrifugation of a blood sample. If the hemoglobin level per deciliter of blood in the patient is high, the physician can infer that the patient has sufficient capacity to carry oxygen to the tissue. During an operation this value is often used as a trigger; i.e. if the value falls below a certain point, additional blood is given to the patient. While these parameters provide an indication of the arterial oxygen content of the blood, they provide no information on the total amount of oxygen transported (or xe2x80x9cofferedxe2x80x9d) to the tissues, or on the oxygen content of blood coming from the tissues.
For example, it has been shown that low postoperative hematocrit may be associated with postoperative ischemia in patients with generalized atherosclerosis. Though a number of researchers have attempted to define a critical Hct level, most authorities would agree that an empirical automatic transfusion trigger, whether based on Hb or Hct, should be avoided and that red cell transfusions should be tailored to the individual patient. The transfusion trigger, therefore, should be activated by the patient""s own response to anemia rather than any predetermined value.
This is, in part, due to the fact that a number of parameters are important in determining how well the patient""s tissues are actually oxygenated. In this regard, the patient""s cardiac output is also an important factor in correlating hemoglobin levels with tissue oxygenation states. Cardiac output or CO is defined as the volume of blood ejected by the left ventricle of the heart into the aorta per unit of time (ml/min) and can be measured with thermodilution techniques. For example, if a patient has internal bleeding, the concentration of hemoglobin in the blood might be normal, but the total volume of blood will be low. In this situation, due to the inadequate venous return of blood to the heart, the cardiac output decreases to provide better circulation to the tissues. Accordingly, simply measuring the amount of hemoglobin in the blood without measuring other parameters such as cardiac output is not always sufficient for estimating the actual oxygenation state of the patient.
More specifically the oxygenation status of the tissues is reflected by the oxygen supply/demand relationship of those tissues i.e., the relationship of total oxygen transport (DO2) to total oxygen consumption (VO2). Hemoglobin is oxygenated to oxyhemoglobin in the pulmonary capillaries and then carried by the cardiac output to the tissues, where the oxygen is consumed. As oxyhemoglobin releases oxygen to the tissues, the partial pressure of oxygen (PO2) decreases until sufficient oxygen has been released to meet the oxygen consumption (VO2). Although there have been advances in methods of determining the oxygenation status of certain organ beds (e.g., gut tonometry; near infrared spectroscopy) these methods are difficult to apply in the clinical setting. Therefore, the use of parameters that reflect the oxygenation status of the blood coming from the tissues i.e., the partial pressure of oxygen in the mixed venous blood (PvO2; also known as the mixed venous blood oxygen tension) or mixed venous blood oxyhemoglobin saturation (SvO2) has become a generally accepted practice for evaluating the global oxygenation status of the tissues.
Unfortunately, relatively invasive techniques are necessary to provide more accurate tissue oxygenation levels. In this respect, direct measurement of the oxygenation state of a patient""s mixed venous blood during surgery may be made using pulmonary artery catheterization. To fully assess whole body oxygen transport and delivery, one catheter (a flow directed pulmonary artery [PA] catheter) is placed in the patient""s pulmonary artery and another in a peripheral artery. Blood samples are then drawn from each catheter to determine the pulmonary artery and arterial blood oxygen levels. As previously discussed, cardiac output may also be determined using the PA catheter. The physician then infers how well the patient""s tissue is oxygenated directly from the measured oxygen content of the blood samples.
While these procedures have proven to be relatively accurate, they are also extremely invasive. For example, use of devices such as the Swan-Ganz(copyright) thermodilution catheter (Baxter International, Santa Ana, Calif.) can lead to an increased risk of infection, pulmonary artery bleeding, pneumothorax and other complications. Further, because of the risk and cost associated with PA catheters, their use in surgical patients is restricted to high-risk or high-blood-loss procedures (e.g., cardiac surgery, liver transplant, radical surgery for malignancies) and high-risk patients (e.g., patients who are elderly, diabetic, or have atherosclerotic disease).
Among other variables, determination of the oxygenation status of the tissues should include assessment of the amount of blood being pumped toward the tissues (CO) and the oxygen content of that (arterial) blood (CaO2). The product of these variables may then be used to provide a measure of total oxygen transport (DO2). Currently, assessment of DO2 requires the use of the invasive monitoring equipment described above. Accordingly, determination of DO2 is not possible in the majority of surgical cases. However, in the intensive care unit (ICU), invasive monitoring tends to be a part of the routine management of patients; thus, DO2 determinations are obtained more readily in this population.
Partial pressure of oxygen in the mixed venous blood or mixed venous blood oxygen tension (PvO2) is another important parameter that may be determined using a PA catheter. Because of the equilibrium that exists between the partial pressure of oxygen (PO2) in the venous blood and tissue, a physician can infer the tissue oxygenation state of the patient. More specifically, as arterial blood passes through the tissues, a partial pressure gradient exists between the PO2 of the blood in the arteriole passing through the tissue and the tissue itself. Due to this oxygen pressure gradient, oxygen is released from hemoglobin in the red blood cells and also from solution in the plasma; the released O2 then diffuses into the tissue. The PO2 of the blood issuing from the venous end of the capillary cylinder (PvO2) will generally be a close reflection of the PO2 at the distal (venous) end of the tissue through which the capillary passes.
Closely related to the mixed venous blood oxygen tension (PvO2) is the mixed venous blood oxyhemoglobin saturation (SvO2) which is expressed as the percentage of the available hemoglobin bound to oxygen. Typically, oxyhemoglobin disassociation curves are plotted using SO2 values vs. PO2 values. As the partial pressure of oxygen (PO2) decreases in the blood (i.e. as it goes through a capillary) there is a corresponding decrease in the oxygen saturation of hemoglobin (SO2). While arterial values of PO2 and SO2 are in the neighborhood of 95 mm Hg and 97% respectively, mixed venous oxygen values (PvO2, SvO2) are on the order of 45 mm Hg and 75% respectively. As such SvO2, like PvO2, is indicative of the global tissue oxygenation status. Unfortunately, like PvO2, it is only measurable using relatively invasive measures.
Another rather informative parameter with respect to patient oxygenation is deliverable oxygen (dDO2). dDO2 is the amount of the oxygen transported to the tissues (DO2) that is able to be delivered to the tissues (i.e. consumed by the tissues) before the PvO2 (and by implication the global tissue oxygen tension) falls below a certain value. For instance the dDO2(40) is the amount of oxygen that can be delivered to the tissues (consumed by the tissues) before PvO2 is 40 mm Hg while dDO2(35) is the amount consumed before the PvO2 falls to 35 mm Hg.
Additional relevant parameters may be determined non-invasively. For instance, whole body oxygen consumption (VO2) can be calculated from the difference between inspired and mixed expired oxygen and the minute volume of ventilation. Cardiac output may also be non-invasively inferred by measuring arterial blood pressure instead of relying on thermodilution catheters. For example, Kraiden et al. (U.S. Pat. No. 5,183,051, incorporated herein by reference) use a blood pressure monitor to continuously measure arterial blood pressure. These data are then converted into a pulse contour curve waveform. From this waveform, Kraiden et al. calculate the patient""s cardiac output.
Regardless of how individual parameters are obtained, those skilled in the art will appreciate that various well established relationships allow additional parameters to be derived. For instance, the Fick equation (Fick, A. Wurzburg, Physikalisch edizinische Gesellschaft Sitzungsbericht 16 (1870)) relates the arterial oxygen concentration, venous oxygen concentration and cardiac output to the total oxygen consumption of a patient and can be written as:
(CaO2xe2x88x92CvO2)xc3x97CO=VO2
where CaO2 is the arterial oxygen content, CvO2 is the venous oxygen content, CO is the cardiac output and VO2 represents whole body oxygen consumption.
While the non-invasive derivation of such parameters is helpful in the clinical setting, a more determinative xe2x80x9ctransfusion triggerxe2x80x9d would clearly be beneficial. If PvO2 or DO2 is accepted as a reasonable indicator of patient safety, the question of what constitutes a xe2x80x9csafexe2x80x9d level of these parameters arises. Though data exists on critical oxygen delivery levels in animal models, there is little to indicate what a critical PvO2 might be in the clinical situation. The available data indicate that the level is extremely variable. For instance, in patients about to undergo cardiopulmonary bypass, critical PvO2 varied between about 30 mm Hg and 45 mm Hg where the latter value is well within the range of values found in normal, fit patients. Safe DO2 values exhibit similar variability.
For practical purposes a PvO2 value of 35 mm Hg or more may be considered to indicate that overall tissue oxygen supply is adequate, but this is implicit on the assumption of an intact and functioning vasomotor system. Similarly, the accurate determination of DO2 depends on an intact circulatory system. During surgery it is necessary to maintain a wide margin of safety and probably best to pick a transfusion trigger (whether DO2, PvO2, SvO2 or some derivation thereof) at which the patient is obviously in good condition as far as oxygen dynamics are concerned. In practice, only certain patients will be monitored with a pulmonary artery catheter. Accordingly, the above parameters will not be available for all patients leaving the majority to be monitored with the imperfect, and often dangerous, trigger of Hb concentration.
Efforts to resolve these problems in the past have not proven entirely successful. For example, Faithfull et al. (Oxgen Transport to Tissue XVI, Ed. M. Hogan, Plenum Press, 1994, pp. 41-49) describe a model to derive the oxygenation status of tissue under various conditions. However, the model is merely a static simulation allowing an operator to gauge what effect changing various cardiovascular or physical parameters will have on tissue oxygenation. No provisions are made for continuous data acquisition and evaluation to provide a dynamic representation of what may actually be occurring. Accordingly, the model cannot be used to provide real-time measurements of a patient""s tissue oxygenation under changing clinical conditions.
Accordingly it is a general object of the present invention to provide systems and methods to accurately assess, in real-time, SvO2, PvO2, DO2, or some derivation thereof, of a patient.
It is a further object of the present invention to provide a method wherein an accurate indication of the oxygenation status of a patient is displayed in real-time without the necessity of invasive intervention.
It is yet another object to provide a single derived value that accurately reflects the oxygenation state of a patient.
These and other objects are accomplished by the methods and systems of the present invention which, in a broad aspect, provide for the real-time determination and display of one or more values that accurately reflect the global oxygenation and cardiovascular status of a patient. Moreover, the present invention provides for determination of the selected values through relatively non-invasive means. As such, the present invention may be used to safely monitor the physiological condition of patients and adjust therapeutic parameters based on the displayed values.
In preferred embodiments, the present invention provides for the determination and real-time display of physiologically important oxygenation parameters indicative of a patient""s tissue oxygenation status such as, for example, total oxygen transport (DO2), deliverable oxygen transport (dDO2), mixed venous blood oxyhemoglobin saturation (SvO2) and mixed venous blood oxygen tension (PvO2). The invention may also be used to provide a supply/demand ratio (dDO2/VO2), another oxygenation paramneter, that allows a physician to accurately monitor and adjust the oxygen status of a patient using a single numerical value. It will be appreciated that the derived oxygenation parameters may be used alone or, more preferably, in combination to provide an indication as to global tissue oxygenation levels. As such, the invention may be used as a uncomplicated, real-time intervention trigger in clinical settings without the risks associated with conventional invasive monitoring equipment.
More specifically, by establishing the minimum acceptable PvO2, SvO2, dDO2 or DO2 for the individual patient, the attending physician is provided with a simple trigger point where intervention is indicated. For example, based on clinical experience a physician may determine that the PvO2 of a patient should not be below 35 mm Hg or that the DO2 should remain above 600 ml/min in order to provide adequate oxygenation. Preferably, the clinician will have access to each of the oxygenation parameters and can display one or more values as desired. In a particularly preferred embodiment, the system will provide a supply/demand ratio (dDO2/VO2) for a selected PvO2 thereby allowing the physician to address the needs of the patient based on a single value. In this embodiment, a value of one or greater indicates the PvO2 (and hence global tissue oxygenation) is higher than the established trigger point.
Particularly preferred embodiments provide a continuous (beat-to-beat) measurement of cardiac output (CO), using inputs from an indwelling catheter placed in a peripheral artery. In this respect an apparatus such as the Modelflow(trademark) system (TNO-Biomedical Instrumentation, Amsterdam), can optionally be used in conjunction with the present invention to provide the CO measurement continuously in real-time. Cardiac output may be computed using an algorithm that simulates the behavior of the human aorta and arterial system via a three-element, nonlinear model of aortic input impedance. Cardiac output computed using this model has been validated against cardiac output determined by thermodilution. In addition to cardiac output, the following hemodynamic information can be derived from systems like Modelflow(trademark) on a beat-to-beat basis: systolic, diastolic, and mean arterial pressure; pulse rate; stroke volume; and peripheral vascular resistance.
The present invention also determines the arterial oxygen content (CaO2) of the patient for use in deriving the desired values. Specifically, in determining the arterial oxygen content (CaO2), the present invention may use one or more numerical values corresponding to the patient""s hemoglobin concentration, arterial oxygen tension (PaO2), arterial carbon dioxide tension (PaCO2), arterial pH and body temperature. These numerical values may be obtained from a blood chemistry monitor or entered manually. Particularly preferred embodiments employ a blood chemistry monitor to obtain the desired values contemporaneously with the measurement of the cardiac output values. Additionally, the oxygen consumption of the patient (VO2) is determined, preferably by gas analysis or metabolic rate determination.
Accordingly, one embodiment of the present invention is relatively non-invasive method for determining, in real-time, one or more oxygenation parameters indicative of tissue oxygenation status of a patient, comprising the steps of:
storing oxygenation constants into a first computer memory;
measuring the cardiac output values (CO) of a patient in real-time, wherein the cardiac output values are saved to a second computer memory;
determining the arterial oxygen content (CaO2) of a said patient; and
calculating, in real-time, said one or more oxygenation parameters indicative of tissue oxygenation status of a patient.
In preferred embodiments the method will further include the step of storing a value corresponding to the whole body oxygen consumption (VO2) of said patient into a third computer memory prior to said calculating step.
Preferably, the first computer memory discussed in the above method is a. random access memory (RAM). Similarly, the second computer memory and third computer memory of the above method are advantageously also random access memories.
In addition to the described methods, the present invention provides a relatively non-invasive apparatus for determining, in real-time, one or more oxygenation parameters indicative of tissue oxygenation status of a patient wherein the apparatus comprises:
a first computer memory for storing oxygenation constants;
an input derived from a relatively non-invasive source reflecting cardiac output (CO) values of a patient in real-time, wherein said cardiac output values are saved in a second computer memory;
first instructions for obtaining the arterial oxygen content (CaO2) of said patient and storing said arterial oxygen content in a third computer memory; and
second instructions for calculating, in real-time, one or more oxygenation parameters indicative of tissue oxygenation status of a patient.
Preferably, the first computer memory, second computer memory and third computer memory are random access memories. In addition, the computer memory can also advantageously be a computer hard disk. Further, the input reflecting the cardiac output can preferably be obtained from an arterial pressure line, transducers or pressure amplifiers. In another embodiment, the first instructions, which may use one or more numerical values to derive the CaO2, can be stored in a blood chemistry monitor. Additionally, the first instructions may employ algorithms for calculating the position of the oxyhemoglobin disassociation curve as provided by the Kelman equations. Preferably the second instructions preferably comprise an application of the Fick equation.
As previously indicated, the present invention further provides methods and apparatus that may be used to monitor the tissue oxygenation status of a patient using a supply/demand ratio. Accordingly, one embodiment of the invention is directed to a relatively non-invasive method for monitoring, in real-time, tissue oxygenation status of a patient comprising the determination of a supply/demand ratio (dDO2/VO2). Similarly, another embodiment is directed to a relatively non-invasive apparatus for determining, in real-time, tissue oxygenation status of a patient, said apparatus comprising instructions for determining a supply/demand ratio (dDO2/VO2). The calculations, values and equipment necessary to provide the desired ratios are as described throughout the instant specification.
In all cases it must be emphasized that, while preferred embodiments of the invention include a blood chemistry monitor and/or pressure transducers (i.e. for CO), they are not essential components of the present invention and are not necessary for practicing the disclosed methods. For example, a physician could manually measure blood gas levels, body temperatures and Hb concentrations and then enter this information into the system via the keyboard. Other methods of measuring cardiac output could be used, such as ultrasound or thoracic impedance.
Those skilled in the art will further appreciate that oxygenation constants are numerical values primarily related to the physical characteristics of oxygen carriers or to the physiological characteristics of the patient. Such oxygenation constants include, but are not limited to, blood volume, oxygen solubility in plasma and the oxygen content of a desired unit of saturated oxyhemoglobin. Preferably one or more oxygenation constants is used in the present invention to derive the selected oxygenation parameters.
From the values obtained using oxygenation constants (for example CaO2, VO2 and CO),the present invention solves the Fick equation [VO2=(CaO2xe2x88x92CvO2)xc3x97CO] by calculating the mixed venous blood oxygen content (CvO2) of the patient. Once the CvO2 has been determined, SvO2 can be calculated and the PvO2 can be readily be derived using algorithms for calculating the position of the oxyhemoglobin disassociation curve such as the Kelman equations (Kelman, J. Appl. Physiol, 1966, 21(4): 1375-1376; incorporated herein by reference). Similarly, other parameters such as DO2, dDO2 and dDO2/VO2 may be derived from the obtained values.
Using the present invention, the clinician could continuously receive real-time data (i.e. the oxygenation parameters discussed above), giving him a complete picture of the patient""s global oxygenation status. Should any of the selected parameters approach the established trigger points, appropriate actions such as pharmacological intervention, fluid loading, blood transfusion or adjustment of the ventilation profile could be undertaken in plenty of time to stabilize the subject. Thus, this continuous flow of data would allow the physician to more readily determine the etiology of the oxygenation decrease (such as, but not limited to, anemia, decreased cardiac output or hypoxia) and tailor the response appropriately.
Other objects, features and advantages of the present invention will be apparent to those skilled in the art from a consideration of the following detailed description of preferred exemplary embodiments thereof taken in conjunction with the Figures which will first be described briefly.